Determine the regulatory sign (activation vs. repression) of transcription factor control

Determine whether a transcription factor positively (activates) or negatively (represses) transcription of a single gene within a complex gene regulatory network when only the existence of regulation is known and the direction of regulation is unresolved.

Background

The paper highlights structural uncertainty in biological modeling, noting that even when regulation between components is established, the direction of that regulation is often unresolved. This uncertainty directly affects the formulation and comparison of mechanistic models, as activation versus repression leads to different mathematical structures and predictions.

Resolving the sign of regulation is crucial for narrowing competing model structures and for accurate mechanistic inference in gene regulatory networks, including the case study presented in the paper.

References

For example, it may be known that a single gene embedded within a complex network is regulated by a transcription factor, but unclear if the regulation is positive or negative in nature.

— Practical indistinguishability in a gene regulatory network inference problem, a case study  (2508.21006 - FitzGerald et al., 28 Aug 2025) in Introduction

Third, although the signed gates are directly inspectable in latent space, translating them into gene-level statements passes through the variational encoder and inherits its seed-dependent non-identifiability, an open problem for VAE-based clustering methods.

— scDNM-VAE enables directly inspectable deep clustering of single-cell RNA-seq data through signed dendritic gating  (2608.17228 - Agraz et al., 18 Aug 2026) in Limitations and future work